1. Field of the Invention
The present invention relates generally to the fields of detection and treatment of cancer. More particularly, it concerns the detection and treatment of multidrug resistant cancers by screening for phingoglycolipids, including glycosylceramides, cerebrosides and gangliosides.
2. Description of Related Art
Clinical resistance to anticancer agents is the principal reason for treatment failure in patients with cancer (Gottesman, 1993). The best-characterized type of drug resistance is classic multidrug resistance (MDR), exhibiting intrinsic resistance to multiple drugs upon primary exposure to a single drug (i.e., vinblastine, adriamycin, taxol, actinomycin D) (Bradley et al., 1988).
Among the multiple biochemical and molecular mechanisms associated with MDR, overexpression of P-glycoprotein (P-gp), a plasma-membrane protein proposed to act as an ATP-driven drug efflux pump, is best studied (Volm et al., 1993; Bradley and Ling, 1994). However, the physiologic function and mechanisms of action of P-gp are largely unknown. Moreover, widespread occurrence of drug resistance in human lung tumors (Cole et al., 1992), which is unrelated to overexpression of P-gp, indicates the existence of additional resistance mechanisms.
The multifactorial nature of MDR is exemplified by a wide array of other biochemical changes including alterations in membrane fluidity and structure (Bradley and Ling, 1994), elevated glutathione S-transferase activity (Bradley and Ling, 1994; Volm et al., 1993), down-regulation of topoisomerase II (Volm et al., 1993), increased phospholipase D activity (Welsh et al., 1994), and elevated transcription of c-fos, c-myc and c-H-ras (Chin et al., 1992; Volm et al., 1993, Sabbatini et al., 1994).
Several associations have been made regarding the role of lipids in drug partitioning, drug transport and drug retention. Reports have shown that P-gp ATPase-activity is dependent on the lipid environment (Doige et al., 1993), and that lipids interact with P-gp substrates (Wadkins and Houghton, 1993; Wright et al., 1985; May et al., 1988; Peterson et al., 1983). Early studies investigated lipid composition of MDR cells as a general feature that may be influential (Holleran et al., 1986; Ramu et al., 1984; May et al., 1988). Differences in lipid composition of drug-sensitive and -resistant cells have been reported, but these were mainly confined to triglycerides, fatty alcohols, and ether lipids, with minor changes in sphingomyelin and phosphatidylcholine (Ramu et al., 1984; Welsh et al., 1994; Wright et al., 1985).
The ganglioside composition of daunorubicin-resistant, vincristine-resistant, and drug-sensitive cells has been examined. Whereas diversity in ganglioside composition was revealed, no definitive correlation to drug resistance was demonstrated (Biedler et al., 1986; Peterson et al., 1983). In other studies, the levels of four major lipid classes, including gangliosides, in doxorubicin-sensitive and -resistant P388 cells, were examined, and no differences in lipid composition were noted (Holleran et al., 1986).
Circumvention of MDR, via re-sensitizing of cells to drug insult, carries major clinical importance (Bradley et al., 1988; Gottesman, 1993). Tsuruo and coworkers showed that a battery of different agents inhibit MDR, rendering cells sensitive to chemotherapy (Tsuruo et al., 1981). Included in this category are the calcium channel blockers verapamil and SR33557 (Tsuruo et al., 1981; Jaffrezou et al., 1991), antiarrhythmic agents like quinidine (Solary et al., 1991), the immunosuppressant cyclosporin A (Slater et al., 1986; Solary et al., 1991), and the anticancer drug tamoxifen (Nayfield, 1995; Kirk et al., 1994).
The mechanism by which these drugs promote influence on MDR cells is thought to be via direct binding of the drug to P-gp with subsequent inhibition of pump activity (Yusa and Tsuruo, 1989; Callaghan and Higgins, 1995). In addition, drugs may exercise effects by modulating other cellular components that subsequently regulate P-gp. For example, selective expression of protein kinase C (PKC) isozymes was correlated with MDR (Blobe et al., 1993), and studies have suggested that P-gp activity can be regulated by PKC (Blobe et al., 1993; Gupta et al., 1996).
Recently, a correlation was demonstrated between inhibition of PKC activity by safingol, and reversal of MDR in MCF-7-doxorubicin resistant cells (Sachs et al., 1995). Also, the calcium channel blocker, SR33557, elicits inhibition of acid sphingomyelinase, and an increase in cellular sphingosine levels which may be correlated with its ability to reverse MDR in P388-adriamycin resistant cells (Jaffrezou et al., 1991). Other work examined a multitude of MDR-circumventing drugs revealing a correlation between inhibition of cellular acid sphingomyelinase activity and tempering of MDR (Jaffrezou et al., 1995).